KLHL40

Summary

KLHL40 (kelch like family member 40, HGNC:30372) is a protein-coding gene on chromosome 3p22.1, encoding Kelch-like protein 40 (Q2TBA0). Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a key regulator of skeletal muscle development.

This gene encodes a protein containing a BACK domain, a BTB/POZ domain, and 5 Kelch repeats, however, its exact function is not known. The gene and the multi-domain protein structure are conserved across different taxa, including primates, rodents, chicken and zebrafish.

Source: NCBI Gene 131377 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nemaline myopathy 8 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 594 total — 27 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes
• MANE Select transcript: NM_152393

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30372
Approved symbol	KLHL40
Name	kelch like family member 40
Location	3p22.1
Locus type	gene with protein product
Status	Approved
Aliases	SRYP, NEM8
Ensembl gene	ENSG00000157119
Ensembl biotype	protein_coding
OMIM	615340
Entrez	131377

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000287777, ENST00000942345, ENST00000942346, ENST00000942347, ENST00000942348, ENST00000942349

RefSeq mRNA: 1 — MANE Select: NM_152393 NM_152393

CCDS: CCDS2703

Canonical transcript exons

ENST00000287777 — 6 exons

Exon	Start	End
ENSE00001030465	42685537	42686770
ENSE00001030470	42688142	42688302
ENSE00001336364	42688610	42688717
ENSE00001348693	42688869	42689054
ENSE00001802949	42690859	42691005
ENSE00001803209	42691882	42692544

Expression profiles

Bgee: expression breadth ubiquitous, 114 present calls, max score 98.74.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.3071 / max 472.4171, expressed in 65 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
36276	1.3071	65

Top tissues by expression

229 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	98.74	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.08	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.05	gold quality
skeletal muscle tissue	UBERON:0001134	96.48	gold quality
muscle of leg	UBERON:0001383	96.47	gold quality
muscle organ	UBERON:0001630	96.35	gold quality
biceps brachii	UBERON:0001507	95.43	gold quality
quadriceps femoris	UBERON:0001377	94.92	gold quality
vastus lateralis	UBERON:0001379	94.84	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.79	gold quality
body of tongue	UBERON:0011876	94.54	gold quality
deltoid	UBERON:0001476	91.14	gold quality
muscle tissue	UBERON:0002385	89.50	gold quality
tongue	UBERON:0001723	84.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.38	silver quality
superior surface of tongue	UBERON:0007371	70.59	gold quality
pharyngeal mucosa	UBERON:0000355	65.75	gold quality
heart left ventricle	UBERON:0002084	59.67	gold quality
right atrium auricular region	UBERON:0006631	59.67	gold quality
cardiac atrium	UBERON:0002081	59.18	gold quality
cardiac ventricle	UBERON:0002082	59.07	gold quality
apex of heart	UBERON:0002098	57.31	gold quality
buccal mucosa cell	CL:0002336	56.69	gold quality
jejunum	UBERON:0002115	56.24	gold quality
heart	UBERON:0000948	55.87	gold quality
trabecular bone tissue	UBERON:0002483	51.50	silver quality
synovial joint	UBERON:0002217	50.86	silver quality
left testis	UBERON:0004533	50.70	gold quality
right testis	UBERON:0004534	50.21	gold quality
testis	UBERON:0000473	49.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting KLHL40, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-6784-3P	98.39	64.88	662
HSA-MIR-6804-5P	98.39	65.77	1084
HSA-MIR-558	97.50	67.16	977
HSA-MIR-490-5P	96.75	65.81	661
HSA-MIR-4793-3P	94.87	65.85	896

Literature-anchored findings (GeneRIF, showing 6)

• KLHL40 mutations as a frequent cause of severe autosomal-recessive nemaline myopathy. It plays a key role in muscle development and function. (PMID:23746549)
• NEB and LMOD3 were reduced in skeletal muscle of KLHL40-deficient patients, providing a potential basis for the development of nemaline myopathy. (PMID:24960163)
• Two compound heterozygous mutations; c.602G > A(p.W201*) and c.1516A > C(p.T506P), in the Kelch-like 40 (KLHL40) gene were discovered in a family with 3 fetuses affected by fetal akinesia deformation sequence. (PMID:27762439)
• The KLHL40 c.1516A>C is a Chinese-specific founder mutation causing nemaline myopathy 8: Report of six patients with pre- and postnatal phenotypes. (PMID:32352246)
• A novel and recurrent KLHL40 pathogenic variants in a Chinese family of multiple affected neonates with nemaline myopathy 8. (PMID:33978323)
• Clinical and molecular analysis of four unrelated Chinese families with pathogenic KLHL40 variants causing nemaline myopathy 8. (PMID:35379254)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	klhl40b	ENSDARG00000019125
danio_rerio	klhl40a	ENSDARG00000039052
mus_musculus	Klhl40	ENSMUSG00000074001
rattus_norvegicus	Klhl40	ENSRNOG00000019390

Paralogs (54): KLHL13 (ENSG00000003096), KLHL20 (ENSG00000076321), KEAP1 (ENSG00000079999), KLHL42 (ENSG00000087448), KLHL22 (ENSG00000099910), KLHL4 (ENSG00000102271), KLHL2 (ENSG00000109466), KLHL5 (ENSG00000109790), BACH2 (ENSG00000112182), KLHL18 (ENSG00000114648), KLHL24 (ENSG00000114796), IVNS1ABP (ENSG00000116679), KLHL12 (ENSG00000117153), KLHL29 (ENSG00000119771), KBTBD7 (ENSG00000120696), KLHL7 (ENSG00000122550), KLHL31 (ENSG00000124743), KLHDC7B (ENSG00000130487), KLHL36 (ENSG00000135686), KLHL8 (ENSG00000145332), KLHL3 (ENSG00000146021), KLHL35 (ENSG00000149243), KLHL1 (ENSG00000150361), BACH1 (ENSG00000156273), KLHL10 (ENSG00000161594), KLHL21 (ENSG00000162413), KLHDC8A (ENSG00000162873), KBTBD8 (ENSG00000163376), KBTBD6 (ENSG00000165572), KLHL26 (ENSG00000167487), KLHL30 (ENSG00000168427), KBTBD2 (ENSG00000170852), KLHL6 (ENSG00000172578), KLHL15 (ENSG00000174010), KLHL38 (ENSG00000175946), KBTBD11 (ENSG00000176595), KLHDC7A (ENSG00000179023), KLHL28 (ENSG00000179454), KBTBD3 (ENSG00000182359), KLHL33 (ENSG00000185271)

Protein

Protein identifiers

Kelch-like protein 40 — Q2TBA0 (reviewed: Q2TBA0)

Alternative names: Kelch repeat and BTB domain-containing protein 5, Sarcosynapsin

All UniProt accessions (1): Q2TBA0

UniProt curated annotations — full annotation on UniProt →

Function. Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a key regulator of skeletal muscle development. The BCR(KLHL40) complex acts by mediating ubiquitination and degradation of TFDP1, thereby regulating the activity of the E2F:DP transcription factor complex. Promotes stabilization of LMOD3 by acting as a negative regulator of LMOD3 ubiquitination; the molecular process by which it negatively regulates ubiquitination of LMOD3 is however unclear.

Subunit / interactions. Component of the BCR(KLHL40) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL40 and RBX1. Interacts with LMOD3.

Subcellular location. Cytoplasm. Myofibril. Sarcomere. A band. I band.

Tissue specificity. Highly expressed in fetal (19, 23 and 31 weeks of gestation) and adult skeletal muscle; expression levels tend to be higher in fetal compared to postnatal muscles (at protein level). Also expressed in fetal and adult heart.

Disease relevance. Nemaline myopathy 8 (NEM8) [MIM:615348] A severe form of nemaline myopathy. Nemaline myopathies are muscular disorders characterized by muscle weakness of varying severity and onset, and abnormal thread-like or rod-shaped structures in muscle fibers on histologic examination. NEM8 is characterized by fetal akinesia or hypokinesia, followed by contractures, fractures, respiratory failure, and swallowing difficulties apparent at birth. Most patients die in infancy. Skeletal muscle biopsy shows numerous small nemaline bodies, often with no normal myofibrils. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the KLHL40 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2TBA0-1	1	yes
Q2TBA0-2	2

RefSeq proteins (1): NP_689606* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000210	BTB/POZ_dom	Domain
IPR006652	Kelch_1	Repeat
IPR011333	SKP1/BTB/POZ_sf	Homologous_superfamily
IPR011705	BACK	Domain
IPR015915	Kelch-typ_b-propeller	Homologous_superfamily
IPR017096	BTB-kelch_protein	Family
IPR030607	KLHL40_BTB/POZ_dom	Domain

Pfam: PF00651, PF07707, PF24681

UniProt features (65 total): strand 29, sequence variant 17, turn 6, repeat 5, domain 2, splice variant 2, chain 1, helix 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4ASC	X-RAY DIFFRACTION	1.78

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2TBA0-F1	89.70	0.77

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 231 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, MEF2_02, FOXO4_01, FOXO1_01, GGGTGGRR_PAX4_03, CAGCTG_AP4_Q5, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (7): negative regulation of protein ubiquitination (GO:0031397), positive regulation of protein ubiquitination (GO:0031398), negative regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032435), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), skeletal muscle fiber development (GO:0048741), skeletal muscle fiber differentiation (GO:0098528)

GO Molecular Function (2): ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), Cul3-RING ubiquitin ligase complex (GO:0031463), A band (GO:0031672), I band (GO:0031674)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
regulation of protein ubiquitination	2
regulation of proteasomal ubiquitin-dependent protein catabolic process	2
proteasome-mediated ubiquitin-dependent protein catabolic process	2
sarcomere	2
negative regulation of protein modification by small protein conjugation or removal	1
positive regulation of protein modification by small protein conjugation or removal	1
negative regulation of proteasomal protein catabolic process	1
negative regulation of ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
skeletal muscle tissue development	1
myotube cell development	1
myotube differentiation	1
skeletal muscle cell differentiation	1
enzyme-substrate adaptor activity	1
binding	1
intracellular anatomical structure	1
cullin-RING ubiquitin ligase complex	1

Protein interactions and networks

STRING

1048 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KLHL40	KBTBD13	C9JR72	878
KLHL40	LMOD3	Q0VAK6	813
KLHL40	TNNT1	P13805	726
KLHL40	TPM2	P06468	696
KLHL40	NEB	P20929	686
KLHL40	MYPN	Q86TC9	623
KLHL40	CUL3	Q13618	609
KLHL40	TPM3	P06753	609
KLHL40	ACTA1	P02568	601
KLHL40	MYO18B	Q8IUG5	588
KLHL40	CFL2	Q9Y281	583
KLHL40	MTM1	Q13496	544
KLHL40	KLHDC2	Q9Y2U9	532
KLHL40	TNNT3	P45378	522
KLHL40	KLHDC1	Q8N7A1	520

IntAct

25 interactions, top by confidence:

A	B	Type	Score
KLHL40	MCM10	psi-mi:“MI:0915”(physical association)	0.670
	KLHL40	psi-mi:“MI:0915”(physical association)	0.560
KLHL40	SAXO1	psi-mi:“MI:0915”(physical association)	0.560
FSD2	KLHL40	psi-mi:“MI:0915”(physical association)	0.560
KLHL40	TASOR2	psi-mi:“MI:0915”(physical association)	0.560
KLHL40	CBX4	psi-mi:“MI:0914”(association)	0.530
KLHL40	NEB	psi-mi:“MI:0915”(physical association)	0.400
KLHL40	SPMIP4	psi-mi:“MI:0915”(physical association)	0.370
SPMIP4	KLHL40	psi-mi:“MI:0915”(physical association)	0.370
CLGN	TMEM131L	psi-mi:“MI:0914”(association)	0.350
FBXO11	ABLIM1	psi-mi:“MI:0914”(association)	0.350
KIRREL1	TNFRSF1A	psi-mi:“MI:0914”(association)	0.350
PTBP3		psi-mi:“MI:0914”(association)	0.350
KLHL40		psi-mi:“MI:0915”(physical association)	0.000
KLHL40	TASOR2	psi-mi:“MI:0915”(physical association)	0.000
KLHL40	SAXO1	psi-mi:“MI:0915”(physical association)	0.000
KLHL40	FSD2	psi-mi:“MI:0915”(physical association)	0.000
KLHL40	MCM10	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (83): KLHL40 (Affinity Capture-MS), KLHL40 (Two-hybrid), KLHL40 (Two-hybrid), KLHL40 (Two-hybrid), KLHL40 (Two-hybrid), C7orf31 (Two-hybrid), KLHL40 (Synthetic Growth Defect), CEP85L (Affinity Capture-MS), ZNF106 (Affinity Capture-MS), ZNF746 (Affinity Capture-MS), DUSP11 (Affinity Capture-MS), ZNF81 (Affinity Capture-MS), KLHL41 (Affinity Capture-MS), SLAIN1 (Affinity Capture-MS), MCM10 (Affinity Capture-MS)

ESM2 similar proteins: A2AAX3, A2AUC9, B3DIV9, D2HEW7, D3ZA50, D3ZZC3, E9QJ30, G3X9X1, O14682, O35709, O60662, Q08BL9, Q0D2A9, Q1LYM6, Q2TBA0, Q2WGJ6, Q3B7M1, Q4KLM4, Q53GT1, Q56A24, Q5EB39, Q5RCQ9, Q5RDY3, Q5RGB8, Q5U504, Q5U575, Q5ZJU2, Q66HD2, Q6DEL7, Q6DFF7, Q6GQU2, Q6NYM1, Q6Q7X9, Q6TFL4, Q6V595, Q8BRG6, Q8BWA5, Q8CA72, Q8IY47, Q8N4N3

Diamond homologs: A0A2R8Q1W5, A9JRD8, B0WWP2, B3DIV9, B3M9V8, B3NDN0, B4GRJ2, B4HIK1, B4J045, B4L0G9, B4LIG6, B4MXW3, B4PD06, B4QLQ2, D3Z8N4, D3ZUU2, E0CZ16, E1B932, E7F6F9, E9Q4F2, F1LZ52, F1LZF0, F1MBP6, G3X9X1, O15062, O93567, O94889, O95198, P28575, P57790, Q04652, Q08DK3, Q13105, Q14145, Q16RL8, Q1ECZ2, Q2M0J9, Q2TBA0, Q3SWU4, Q3ZB90

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

594 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	13
Uncertain significance	312
Likely benign	197
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1172562	NM_152393.4(KLHL40):c.1608-1G>A	Pathogenic
1320051	NM_152393.4(KLHL40):c.1281_1294del (p.Cys428fs)	Pathogenic
1388572	NM_152393.4(KLHL40):c.58C>T (p.Gln20Ter)	Pathogenic
1405293	NM_152393.4(KLHL40):c.223G>T (p.Glu75Ter)	Pathogenic
1411479	NM_152393.4(KLHL40):c.928del (p.Leu310fs)	Pathogenic
1454686	NM_152393.4(KLHL40):c.173del (p.Phe58fs)	Pathogenic
1458028	NM_152393.4(KLHL40):c.205_214del (p.Ala69fs)	Pathogenic
1971874	NM_152393.4(KLHL40):c.275C>G (p.Ser92Ter)	Pathogenic
2176697	NM_152393.4(KLHL40):c.1292C>A (p.Ser431Ter)	Pathogenic
2576958	NM_152393.4(KLHL40):c.270C>G (p.Tyr90Ter)	Pathogenic
2703307	NM_152393.4(KLHL40):c.1608-1G>C	Pathogenic
2826151	NM_152393.4(KLHL40):c.1450dup (p.Asp484fs)	Pathogenic
3652953	NM_152393.4(KLHL40):c.1302C>A (p.Cys434Ter)	Pathogenic
3720495	NM_152393.4(KLHL40):c.134del (p.Pro45fs)	Pathogenic
4727795	NM_152393.4(KLHL40):c.301_304dup (p.Gln102fs)	Pathogenic
4750508	NM_152393.4(KLHL40):c.586G>T (p.Glu196Ter)	Pathogenic
4778318	NM_152393.4(KLHL40):c.815dup (p.Lys273fs)	Pathogenic
541327	NM_152393.4(KLHL40):c.1395C>A (p.Tyr465Ter)	Pathogenic
60513	NM_152393.4(KLHL40):c.1405G>T (p.Gly469Cys)	Pathogenic
60514	NM_152393.4(KLHL40):c.602G>T (p.Trp201Leu)	Pathogenic
60515	NM_152393.4(KLHL40):c.1612G>C (p.Ala538Pro)	Pathogenic
60516	NM_152393.4(KLHL40):c.602G>A (p.Trp201Ter)	Pathogenic
650910	NM_152393.4(KLHL40):c.818dup (p.Lys275fs)	Pathogenic
658674	NM_152393.4(KLHL40):c.631del (p.Ala211fs)	Pathogenic
846771	NM_152393.4(KLHL40):c.1516A>C (p.Thr506Pro)	Pathogenic
952701	NM_152393.4(KLHL40):c.544_545del (p.Ser182fs)	Pathogenic
961304	NM_152393.4(KLHL40):c.211G>T (p.Glu71Ter)	Pathogenic
1510362	NM_152393.4(KLHL40):c.1607+1G>T	Likely pathogenic
1675302	NM_152393.4(KLHL40):c.1350C>A (p.Tyr450Ter)	Likely pathogenic
2180504	NM_152393.4(KLHL40):c.1152+1G>A	Likely pathogenic

SpliceAI

1385 predictions. Top by Δscore:

Variant	Effect	Δscore
3:42686744:G:GT	donor_gain	1.0000
3:42686808:GGCTC:G	donor_gain	1.0000
3:42686809:GCTC:G	donor_gain	1.0000
3:42688140:A:AG	acceptor_gain	1.0000
3:42688141:G:GG	acceptor_gain	1.0000
3:42688141:GTTT:G	acceptor_gain	1.0000
3:42688300:GCT:G	donor_gain	1.0000
3:42688718:G:C	donor_loss	1.0000
3:42688719:T:G	donor_loss	1.0000
3:42688867:A:AG	acceptor_gain	1.0000
3:42688868:G:GG	acceptor_gain	1.0000
3:42688868:GGAA:G	acceptor_gain	1.0000
3:42689029:G:GT	donor_gain	1.0000
3:42689055:G:GG	donor_gain	1.0000
3:42691001:TGGAG:T	donor_gain	1.0000
3:42691002:GGAG:G	donor_gain	1.0000
3:42691002:GGAGG:G	donor_gain	1.0000
3:42691003:GAG:G	donor_gain	1.0000
3:42691003:GAGG:G	donor_gain	1.0000
3:42691006:G:GG	donor_gain	1.0000
3:42691006:GTGA:G	donor_loss	1.0000
3:42691007:T:A	donor_loss	1.0000
3:42691877:CCCA:C	acceptor_loss	1.0000
3:42691878:CCAGG:C	acceptor_loss	1.0000
3:42691880:A:T	acceptor_loss	1.0000
3:42692874:CC:C	acceptor_gain	1.0000
3:42692875:CCTG:C	acceptor_gain	1.0000
3:42693071:CCTCA:C	donor_loss	1.0000
3:42693072:CTCA:C	donor_loss	1.0000
3:42693073:TCA:T	donor_loss	1.0000

AlphaMissense

4061 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:42685781:A:C	S55R	0.998
3:42685783:C:A	S55R	0.998
3:42685783:C:G	S55R	0.998
3:42688620:T:A	W442R	0.998
3:42688620:T:C	W442R	0.998
3:42688915:T:A	W490R	0.998
3:42688915:T:C	W490R	0.998
3:42686675:A:C	S353R	0.997
3:42686677:C:A	S353R	0.997
3:42686677:C:G	S353R	0.997
3:42688163:T:A	W392R	0.997
3:42688163:T:C	W392R	0.997
3:42690860:T:A	W537R	0.997
3:42690860:T:C	W537R	0.997
3:42689035:T:G	Y530D	0.996
3:42690891:G:C	R547P	0.996
3:42691904:T:A	W593R	0.996
3:42691904:T:C	W593R	0.996
3:42685791:T:C	F58S	0.995
3:42685978:C:G	C120W	0.995
3:42688622:G:C	W442C	0.995
3:42688622:G:T	W442C	0.995
3:42688917:G:C	W490C	0.995
3:42688917:G:T	W490C	0.995
3:42688946:G:C	R500P	0.995
3:42690890:C:A	R547S	0.995
3:42690944:T:C	F565L	0.995
3:42690946:T:A	F565L	0.995
3:42690946:T:G	F565L	0.995
3:42685674:T:C	L19P	0.994

dbSNP variants (sampled 300 via entrez): RS1000008527 (3:42685453 T>A,C), RS1000247560 (3:42685149 G>A,C,T), RS1000585282 (3:42690084 G>A), RS1000728499 (3:42692695 G>A), RS1000760096 (3:42692469 G>A), RS1000809558 (3:42688820 T>A,C,G), RS1001389596 (3:42687728 G>A,C), RS1001548495 (3:42691439 A>G), RS1001561923 (3:42689746 CAA>C,CA), RS1001666466 (3:42684664 T>C), RS1001680315 (3:42684027 C>G), RS1002711823 (3:42691718 G>A,T), RS1002981690 (3:42686965 G>T), RS1003955831 (3:42690811 T>A,C), RS1004240706 (3:42685766 G>A,T)

Disease associations

OMIM: gene MIM:615340 | disease phenotypes: MIM:615348

GenCC curated gene-disease

Disease	Classification	Inheritance
nemaline myopathy 8	Definitive	Autosomal recessive
severe congenital nemaline myopathy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nemaline myopathy 8	Definitive	AR

Mondo (2): nemaline myopathy 8 (MONDO:0014138), severe congenital nemaline myopathy (MONDO:0015735)

Orphanet (1): Severe congenital nemaline myopathy (Orphanet:171430)

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000239	Large fontanelles
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000508	Ptosis
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000765	Abnormal thorax morphology
HP:0000775	Abnormality of the diaphragm
HP:0000883	Thin ribs
HP:0001181	Adducted thumb
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001319	Neonatal hypotonia
HP:0001324	Muscle weakness
HP:0001337	Tremor
HP:0001349	Facial diplegia
HP:0001371	Flexion contracture
HP:0001522	Death in infancy
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001622	Premature birth
HP:0001623	Breech presentation
HP:0001640	Cardiomegaly
HP:0001644	Dilated cardiomyopathy
HP:0001695	Cardiac arrest
HP:0001762	Talipes equinovarus
HP:0001989	Fetal akinesia sequence

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004250_50	Alanine aminotransferase (ALT) levels after remission induction therapy in actute lymphoblastic leukemia (ALL)	5.000000e-06
GCST007293_127	Body fat distribution (arm fat ratio)	3.000000e-06
GCST007294_148	Body fat distribution (trunk fat ratio)	3.000000e-08
GCST007294_87	Body fat distribution (trunk fat ratio)	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007965	response to combination chemotherapy
EFO:0004341	body fat distribution

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6196093 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
terbufos	increases methylation	1
aflatoxin B2	increases methylation	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Valproic Acid	affects expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL6094272	Binding	Binding affinity to KBTBD5 (unknown origin) at 10 uM by thermal shift assay	Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F0YL	GM29206	Induced pluripotent stem cell	Male
CVCL_HQ48	GM25494	Transformed cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.